A Novel Strategy for the Treatment of Aneurysms: Inhibition of MMP-9 Activity through the Delivery of TIMP-1 Encoding Synthetic mRNA into Arteries

• Published in: International journal of molecular sciences 2024-06, Vol.25 (12), p.6599
• Main Authors: Golombek, Sonia, Doll, Isabelle, Kaufmann, Louisa, Lescan, Mario, Schlensak, Christian, Avci-Adali, Meltem
• Format: Article
• Language: English
• Subjects: aneurysm; Aneurysm - genetics; Aneurysm - therapy; Aneurysms; Animals; Aorta - metabolism; Aortic aneurysms; Arteries; Arteries - metabolism; Blood vessels; cardiovascular diseases; cardiovascular interventions; Collagen; Coronary vessels; Development and progression; Drug therapy; Elastin; Ethylenediaminetetraacetic acid; Fibroblasts; Humans; Inflammation; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; Messenger RNA; Mortality; Physiology; Protein expression; protein replacement therapies; Proteins; Proteolysis; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; Scientific equipment and supplies industry; synthetic mRNA; TIMP-1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Veins & arteries
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25126599

Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no satisfactory or clinically effective pharmaceutical treatments for this condition. Accelerated inflammatory processes during aneurysm development lead to increased levels of matrix metalloproteinases (MMPs) and destabilization of the vessel wall through the degradation of the structural components of the extracellular matrix (ECM), mainly collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) directly regulate MMP activity and consequently inhibit ECM proteolysis. In this work, the synthesis of TIMP-1 protein was increased by the exogenous delivery of synthetic TIMP-1 encoding mRNA into aortic vessel tissue in an attempt to inhibit MMP-9. In vitro, TIMP-1 mRNA transfection resulted in significantly increased TIMP-1 protein expression in various cells. The functionality of the expressed protein was evaluated in an appropriate ex vivo aortic vessel model. Decreased MMP-9 activity was detected using in situ zymography 24 h and 48 h post microinjection of 5 µg TIMP-1 mRNA into the aortic vessel wall. These results suggest that TIMP-1 mRNA administration is a promising approach for the treatment of aneurysms.